High level of uric acid, or hyperuricemia is a metabolic disease caused by the increased level of uric acid in blood resulting from metabolic disorder of a substance in human body called purine. The production and excretion of uric acid in vivo are approximately in equal amounts. As to the production amount, one third is derived from foods, while two thirds is self-synthesized in vivo. As to the excretion pathway, one third is excreted by the intestinal tracts, while two thirds is excreted from the kidney. The level of uric acid will increase so long as any of the pathways mentioned above goes wrong. The increase in the level of uric acid will impede the secretion process of uric acid in blood so that uric acid could not be excreted. If the level of uric acid is too high, some other diseases may occur, such as gout, nephropathy and cardiovascular diseases.
High level of uric acid would cause gout. Gout is a kind of arthritis with recurrent episodes which results from the increased level of blood uric acid due to metabolic disorder of purine in human body. High level of uric acid would also cause gouty nephropathy, which is the kidney damage caused by hyperuricemia due to the excessive generation of blood uric acid without proper excretion. Patients having the severe hyperuricemia would have renal failure. Gout is a group of heterogeneous conditions with tissue injuries caused by the increase of blood uric acid. It is caused by metabolic disorder of purine in vivo and/or reduced excretion of uric acid, and exhibits episodes of hyperuricemia. The uric acid content in plasma of healthy people is 20-60 mg/L. When it exceeds 80 mg/L, urate crystals will be deposited at parts of human body like joints, soft tissues and kidney, and the resulting crystal precipitation will lead to arthritis, lithangiuria and kidney diseases, namely, “gout”. Upon acute onset, urate microcrystals are deposited at joints, thus causing local granulocyte infiltration s and inflammatory responses. Upon recurrent onsets, joint deformity occurs with “tophi” formed. Gout has been a common disease in western countries and Japan for a long time. In recent years, gout has also become an epidemic in China (particularly in coastal regions).
The existing researches suggest that the acute onset of gout is an acute inflammatory process induced by urate crystals, which starts with the interactions between urate crystals and resident monocytes/macrophages, and finally spontaneously alleviates with several underlying mechanisms through a series of inflammatory responses. In most patients, the gout outbreak is related with the changing (increasing or decreasing) rate of blood uric acid level, yet irrelevant to the stable level of blood uric acid. The abrupt change of the blood uric acid level may bring changes in volume or shape to the crystals so that the crystals may move in tissue matrices, which would promote the release of urate crystals from the body parts where the formed tophi are deposited. It is the released microcrystals or the crystals newly formed locally that cause the inflammatory responses. The interactions between monocytes/macrophages and urate crystals are the key step to initiate the onset of acute gout. The interactions between urate crystals and resident macrophages initiate inflammatory responses and induce the infiltration of neutrophil granulocytes and monocytes to enhance inflammatory responses.
The onset of acute gout involves a number of inflammatory factors which mainly include chemokines such as IL-1β IL-6 IL-18 TNF-α and IL-8 (CXCL-8). By determining the levels of inflammatory factors and anti-inflammatory factors in the joint fluids of patients at different stages of acute gout, it is found that at the early and middle stages of inflammation, there are the significant increases in the levels of inflammatory factors such as IL-1β IL-6 and TNF-α and in the level of leukocytes within joint fluids.
At present, IL-1 is also known as lymphocyte stimulator, and is mainly produced by the activated monocyte-macrophage. The IL-1 has two different molecular forms, IL-1α and IL-1β. IL-1α and IL-1β synergistically stimulates the activation of antigen-presenting cells and T-cells and promotes proliferation of B cells and secretion of antibodies at low local concentrations, providing immune modulation. The precursor of IL-1β is produced by immune cells such as monocyte-macrophages and dendritic cells, and is converted to the activated IL-1β by Caspase-1 within NALP3 inflammasome complex. The activated IL-1β is released to mediate the inflammatory responses. IL-1β could trigger the release of IL-6 and IL-8 and mediate the infiltration of neutrophil granulocytes. Besides, the rapid clinical responses of acute gout patients against various IL-1 inhibitors also demonstrate the critical role of this factor in gout inflammations. The recent research data show that interleukin 1β (IL1β) plays an important role in the inflammation process caused by the deposition of sodium urate (MSU) crystals in gout patients (Ann Rheum Dis 2009; 68: 1613-1617).
TNF-α (tumor necrosis factor) is a polypeptide-typed cytokine produced by monocytes and macrophages, and plays an important role in inflammatory responses, development of immune systems, programmed cell death and lipid metabolism. TNF-α is also involved in the development of diseases including asthma, Crohn's disease, rheumatoid arthritis, neuropathic pain, obesity, type II diabetes, autoimmune diseases and tumors. In the immune responses, TNF-α is a multifunctional regulator and even serves as a strong pyrogenic substance to stimulate neutrophil granulocytes, to change the behaviors of vascular endothelial cells, and to regulate the metabolic activity of some tissues.
IFN-γ (interferon γ) is a glycoprotein produced by T cells and natural killer cells in the immune system, and it can activate macrophages to secrete a higher level of pro-inflammatory cytokines and a lower level of anti-inflammatory cytokines so as to improve bactericidal and tumoricidal activity of macrophages.
A common physical sign among gout patients is that the uric acid concentration in blood increases pathologically. Although not all people with an elevated uric acid level would suffer from gout, each gout patient does have an increased uric acid level. The uric acid concentration increases for two reasons. The first is the reduced urinary excretion of uric acid, and the second one is the enhanced biosynthesis of uric acid due to regulation disorders.
Gout is divided into primary gout and secondary gout. The former is mainly caused by enzyme deficiency, often accompanied by hypertension, diabetes, hyperlipidemia, obesity, metabolic syndrome and coronary heart disease, and may be passed on to his/her offspring. The latter is caused by nephropathy, blood disease, medication and other causes.
If gout is not actively prevented or treated properly, gout will deteriorate with more joints attacked and occur morefrequently, leading to gout based heterogeneous diseases. Urate crystals are deposited on the joints to trigger acute goutarthritis. As multiple joints are attacked at the same time, gout will develop into chronic (long-term) arthritis. Repeated occurrences will cause permanent damages to the joints, including long-term pain and stiffness, limited mobility and joint deformity. When the condition progresses, the crystals will be deposited in soft tissues and then form subcutaneously lumps called “tophi”. The deposition of crystals in kidney may cause kidney lesions, leading to acute uric acid nephropathy, chronic urate nephropathy, which causes severe kidney damage and generation of uric acid stones in urinary system.

The gouty arthritis is high in incidence, difficult to cure, and occurs over and over. Patients suffer a lot from various complications. This disease is considered as one of the top ten stubborn diseases of the 21st century by World Health Organization.
Many epidemiological studies have so far confirmed that high blood uric acid is an independent risk factor for hypertension. A blood uric acid level increase by 1 mg/dL correlates with an increase of the relative risk of hypertension by 25%. Long-term hyperuricemia may damage pancreatic β-cell's functions and induce diabetes, and studies have shown that there is a causal relationship between long-term hyperuricemia and impaired glucose tolerance as well as diabetes occurrence.
Uric acid level is an independent risk factor for death caused by coronary heart disease. Studies have shown that regardless of gender, uric acid is an independent risk factor for death caused by coronary heart disease. A blood uric acid increase by 1 mg/dL correlates with an increase in the risk of death by 48% for men and 126% for women. Blood uric acid content of more than 6 mg/dL is an independent risk factor for occurrence of coronary heart disease. Blood uric acid content of more than 7 mg/dL is an independent risk factor for stroke occurrence.
Uric acid level and kidney disease are closely related. In addition to the aggravated renal damages resulting from the inflammation at renal arteriolar and chronic inflammation at interstitial caused by the deposition of uric acid crystals, many epidemiological investigations and animal studies have shown that uric acid can directly cause microvascular lesions at afferent arteriolar, leading to chronic kidney disease.
At present, there are limited types of anti-gout agents. Clinical treatment of gout mainly involves the administration of colchicine, agents inhibiting uric acid synthesis (allopurinol, febuxostat), agents promoting uric acid excretion (e.g., probenecid, sulfinpyrazone, benzbromarone, Lesinurad), non-steroidal anti-inflammatory agents and hormones. For acute onset, colchicine, non-steroidal anti-inflammatory agents and hormones are mainly used. When conditions are alleviated, agents inhibiting uric acid synthesis and agents promoting uric acid excretion are mainly used. However, these agents are not so good for treatment because of poor efficacy and adverse side effects.
In 2012, the first-choice uric acid-lowering agents recommended by American College of Rheumatology (ACR) in the Guide to Gout Therapy were allopurinol and febuxostat, wherein febuxostat was recommended for the first time as a first-choice agent. Probenecid serves as a first-choice agent to promote uric acid excretion in the uric acid-lowering treatment only when the patient cannot take or cannot tolerate at least one of the xanthine oxidase inhibitors. In addition, the ACR guidelines recommend the patient starts to receive uric acid-lowering therapy immediately after effective anti-inflammatory therapy begins.
Therefore, there are still needs for new agents for the treatment or prevention of uratic or gouty diseases.
WO2005077950 discloses the compound of general formula (I) of the present invention for treatment of diseases such as dyslipidemia, type II diabetes and the like by activating HM74A (also known as GPR109A). However, this patent does not disclose or suggest that the compound can be useful in the prevention or treatment of uratic or gouty diseases.
WO2011057110 discloses that xanthine derivatives prevent or treat diseases such as cerebral ischemia and the like by activating HM74A.
US20130150383 discloses the use of xanthine compounds for treatment of psoriasis.
US2015080418A1 discloses the use of xanthine compounds in treatment of disorders of nervous tissue.
WO9316699A1 discloses the use of xanthine compounds for treatment of fungal infections.
WO9920280A1 discloses the use of xanthine compounds for treatment of cutaneous itching.
EP0389282A2 discloses the effects of xanthine compounds on brain metabolism, neuroprotection, and vascular abnormalities.
One literature (Expert Opin. Ther Patents 2009, 19 (7), 957-967) discloses that xanthine derivatives activate GPR109A for treatment of dyslipidemia, type II diabetes and some other diseases.
One literature (Curr Atheroscler Rep 2013, 15:325, 1-10) discloses that GPR109A has a pharmacological effect of mediating vascular inflammation.
One literature (PLoS One. 2014 Oct. 17; 9 (10): e109818) indicates that GPR109A is effective in treating Parkinson's disease.
However, none of these literatures has reported the role of xanthine compounds in reducing uric acid level, preventing or treating gout.